Molecular genetics and dysmorphology

Question 1

Human genome sequence classes

Answer 1

Single copy sequences (non-repetitive) - genes

Repetitive - interspersed repeats (Alu repeats); satellite DNA (large blocks of repetitive sequence, heterochromatin)

Question 2

How do genes evolve?

Answer 2

Duplication and divergence

Question 3

What are processed genes?

Answer 3

Intronless copies of other genes - usually from remote parent genes.
Reverse transcription and reintegration usually causes e.g. retroviruses
Most are non-functional

Question 4

Classifications of repetitive DNA

Answer 4

Satellite DNA are large blocks of repeat DNA sequences

Interspersed repeats are scattered around the genome

Question 5

Satellite DNA

Answer 5

Large blocks at centromeres and heterochromatic chromosomal regions. Simple tandemly repeated sequences.
Many types e.g. Alphoid DNA centromere repeat, chromosome specific

Question 6

Alphoid DNA

Answer 6

Type of satellite DNA found at centromeres
171-bp repeat unit
Repeat unit sequences shows chromosome specific sequence variation.
Alphoid DNA is required for assembly of the centromere.
Remember can be chromosome specific.

Question 7

Interspersed repeats

Answer 7

Scattered around the genome. Individual copies are present at many locations either between or within genes.

Alu repeat: 500k repeats, 300bp, 5% of genome
Dispersed by retrotransposition. Role in generation of molecular pathology.

Question 8

What can go wrong?

Answer 8

Problems with alignment/recognition
Interspersed repeats which unequally crossover
Mutations: deletions/insertions; gross rearrangements; point mutations; trinucleotide repeat expansions

Question 9

Example of large deletions

Answer 9

DMD

Question 10

Example of large duplication

Answer 10

Charcot-Marie-Tooth Disease

Question 11

Example of gross rearrangement

Answer 11

Haemophilia A

Question 12

Haemophilia A mutation description

Answer 12

Turns back on itself and the inverted segment then binds in place

Question 13

Common silent point mutation name

Answer 13

Polymorphism

Question 14

Point mutation changing aa name

Answer 14

Missense

Question 15

Hypermutability of CpG dinucleotides mechanisms

Answer 15

Methylation
Deamination
Mismatch repair

Question 16

What is one-third of mutations

Answer 16

CG->TG

Question 17

Point mutation changing aa to a non-existent sequences name

Answer 17

Nonsense

Makes truncated protein which can be exploited for mutation detection

Question 18

Frameshift mutation

Answer 18

Alter protein sequence beyond mutation which may truncate protein

Question 19

Reference sequence for: genomic DNA

Answer 19

g.

Question 20

Reference sequence for: cDNA

Answer 20

c.

Question 21

Reference sequence for: Protein

Answer 21

p.

Question 22

Trinucleotide repeat expansions

Answer 22

Polyglutamine repeats (CAG)
Large non-coding repeat expansions
Mutational instability

Question 23

Polyglutamine repeats (CAG)

Answer 23

Huntington’s disease

Spinocerebellar ataxias

Question 24

Large non-coding repeat expansions

Answer 24

Fragile X syndrome (CGG repeat expansion)

Myotonic dystrophy

Question 25

Mutational instability

Answer 25

Occasional e.g. Huntington’s

Frequent e.g. Fragile X

Question 26

Morphology definition

Answer 26

The scientific study of the structure and form of either animals and plants or words and phrases - mainly face

Question 27

Congenital malformations prevalence

Answer 27

2-3% of births

Question 28

22q11.2 deletion - prevalence, affects, signs & symptoms

Answer 28

Very variable
1in5k
Learning difficulties in 70%
Congenital heart defect in 75%
Cleft palate 15%
Velopharyngeal insufficiency 32%

Question 29

Achondroplasia - prevalence, affects, signs & symptoms

Answer 29

1in20k
Autosomal dominant
Risk increases with paternal age
Rhizomelic limb shortening
Short stature
Foreamen magnum compression/hydrocephalus

Question 30

Beckwith-Wiedemann Syndrome - prevalence, affects, signs & symptoms

Answer 30

1in10k 
Large tongue
Eat pits/creases
Exomphalos
Hemihypertrophy
Neonatal hypoglycaemia
Increased risk of Wilms tumour (nephroblastoma)

Question 31

Down Syndrome - prevalence, affects, signs & symptoms

Answer 31

Commonest chromosomal disorder
1in800 live births
Learning difficulties
Congenital heart defects
Hypotonia in neonates
SIngle palmar crease
Cataracts
Hearing impairment
Hypothyroidism
Leukaemia
Atlanto-axial instability
Alzheimer's disease

Question 32

Single palmar crease is associated with?

Answer 32

Down syndrome

Question 33

Kabuki syndrome - prevalence, affects, signs & symptoms

Answer 33

1 in 30k

Learning difficulties
Congenital heart disease (50%)
Poor growth
Hearing impairment

Cleft palate
Premature breast development
Persistent fetal finger pads (96%)

Question 34

What is a persistent foetal finger pad?

Answer 34

Prominent ventral soft tissue on finger tips or toes

Question 35

What is Mosaicism?

Answer 35

Hypo / hyper pigmented patches

May follow Blaschko’s lines

Diagnosis via skin biopsy

Question 36

Peutz-Jeghers syndrome - prevalence, affects, signs & symptoms

Answer 36

1 in 50k

GI polyps - bleeding&obstruction

Malignancies: colorectal, gastric, pancreatic, breast, ovarian

Question 37

Treacher-Collins Syndrome - prevalence, affects, signs & symptoms

Answer 37

1 in 50k
Autosomal dominant

Variable presentation

Cleft palate
Hearing impairment

Question 38

Waardenburg syndrome - prevalence, affects, signs & symptoms

Answer 38

1 in 250k

Sensorineural hearing impairment
Iris heterochromia
Premature greying
White forelock
Skin hypopigmentation
Congenital malformations (Hirschsprungs/VSD)

Question 39

William’s Syndrome - chromosome change, prevalence, affects, signs & symptoms

Answer 39

7q11 deletion

1 in 20k

Learning difficulties
‘Cocktail party speech’
Congenital heart disease - (supravalvular aortic stenosis, peripheral pulm. artery stenosis)
Hypercalcaemia